Four sponsors who have ongoing clinical trials evaluating investigational gene therapies to treat Duchenne muscular dystrophy (DMD) joined forces with international experts to better understand the serious adverse events that have occurred during the trials, minimize their recurrence, and assess potential therapeutic and preventative strategies.

The main finding of the collaboration, presented as a poster at the 2022 Muscular Dystrophy Association Clinical & Scientific Conference, was that an anti-transgene mechanism and associated risk factors are probably responsible for the severe adverse events observed during the trials.

“This collaborative approach and its conclusions may have implications to mitigate risks in gene therapy development programs beyond DMD,” the authors of the poster wrote.

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The severe adverse events observed during the trials included leg and bulbar muscle weakness with variable cardiac involvement, in which case cardiac troponin-I levels were increased. These “occurred with a strikingly similar clinical presentation and time course,” the researchers said.

Since the serious adverse events that occurred across different investigational products were very similar, the authors concluded that they were likely unrelated to the type of capsid or promoter used. Instead, they suggested that a T-cell mediated immune response to the transgene protein encoded by the shortened version of the DMD gene contained in the gene therapies was most likely the cause of the adverse events.

The researchers reported that serious adverse events occurred in patients who have a deletion in the portion of the DMD gene that encodes for the N-terminal epitope of the dystrophin protein. In other words, they occurred in patients who lacked this N-terminal epitope, which is present in the transgenic protein. This, the researchers think, could be “resulting in a cross-reactive immunological material (CRIM)-negative setting”.

They now plan to further investigate the immune mechanism and risk factors associated with the occurrence of serious adverse events.


Bonnemann C, Belluscio B, Braun S, et al. A collaborative analysis by clinical trial sponsors and academic experts of anto-transgene SAEs in studies of gene therapy for DMD. Poster presented at: 2022 Muscular Dystrophy Association Clinical & Scientific Conference; March 13-16, 2022; Nashville, TN. Poster 44.